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A brother and sister of Pakistani origin suffered from sensorineural deafness, diabetes mellitus and a macrocytic anaemia. Their bone marrows showed megaloblastic erythropoiesis and contained many ringed sideroblasts. Electron microscope studies of the bone marrow revealed (1) iron-laden mitochondria in many erythroblasts, (2) non-specific abnormalities indicative of dyserythropoiesis in some erythroblasts, and (3) evidence of ineffective erythropoiesis. The deoxyuridine suppression test indicated that the megaloblastic changes were not caused by an impairment of the methylation of deoxyuridylate. Studies of nucleic acid synthesis in the bone marrow cells showed that the rate of incorporation of [3H]thymidine into DNA was increased and that the rates of incorporation of [14C]glycine and [14C]adenine into both DNA and RNA were essentially within the normal range. The anaemia did not respond to therapy with hydroxocobalamin, folic acid or pyridoxine but responded to 25 mg thiamine, daily, by mouth. In one of the cases a post-thiamine marrow aspirate showed a considerable improvement in both the megaloblastic and sideroblastic changes.

In the two preceding papers we discussed the normal hypothalamic integration of energy balance with the sex cycle in the rat, both as seen in the adult and during growth. In the course of this work we observed abnormal rhythms involving the same variables. Such abnormal cycles have been described before, but in different circumstances, and have been shown to consist of a succession of pseudopregnancies (Van der Lee & Boot, 1955;Richter, 1957). In this short paper we wish simply to record the factors which appeared to precipitate these cycles and to consider the possible mechanism. METHODSThe animals and methods have been described in the preceding papers (Kennedy & Mitra, 1963a, b). RESULTSAbnormal cycles after food restriction. In earlier experiments 25 young rats between 60 and 110 days old were underfed by being given half their normal food ration for 10 days. The immediate effects have been described (Kennedy & Mitra, 1963 a); after re-feeding the rats behaved quite normally until they were between 130 and 240 days old. The first sign of abnormality was a decrease in running activity and a break in oestrous cycle, with a little increase in food intake and gain in body weight. The length of the break in cycle varied from rat to rat, the extremes being 12 and 21 days. After a variable period of normal activity there was another interruption of the cycle, then a normal interval and so on for the rest of the rat's life (Fig. 1). The length of the inactive periods were fairly constant in any given rat; the normal intervals were more variable.So far as changes in energy balance were concerned the subsequent history of the rats could be divided into two types. The first is illustrated in Fig. 1. Although in the recovery periods the rat tended to eat rather less than normal and to lose weight, it did not come back to its original level. Moreover, with each successive break in cycle the overeating became more

Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily intravenous injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [ 125 I]-para-iodoclonidine, a radioligand with specificity for high affinity α2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared to prenatal saline controls. As α 2 -adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.